Table 2.
Overview of approved PDE4 inhibitors and next generation PDE4B/D selective inhibitors in late-stage clinical development
| Compound | Indication | Phase | Isoform data | Selectivity ratioa | PDE4 profileb |
|---|---|---|---|---|---|
| Roflumilast (oral and topical) | COPD | Approved |
PDE4A1: 0.7 nM PDE4A4: 0.9 nM PDE4B1: 0.7 nM PDE4B2: 0.2 nM cPDE4C1: 3 nM cPDE4C2: 4.3 nM PDE4D2: 0.3 nM PDE4D3: 0.4 nM PDE4D4: 0.2 nM PDE4D5: 0.4 nM |
PDE4 A/B = 1.8 PDE4 A/D = 2.5 PDE4 B/D = 1.4 Unselective |
High-potency, unselective PDE4 inhibitor |
| Apremilast (oral) | Psoriasis, psoriatic arthritis, and Behcet’s disease | Approved |
PDE4A1: 78 nM PDE4A4: 42 nM PDE4A10: 140 nM PDE4B1: 61 nM PDE4B2: 97 nM PDE4B3: 117 nM cPDE4C2: 244 nM PDE4D1: 44 nM PDE4D2: 54 nM PDE4D3: 54 nM PDE4D4: 41 nM PDE4D5: 61 nM PDE4D7: 50 nM |
PDE4 A/B = 1.0 PDE4 A/D = 1.7 PDE4 B/D = 1.8 Unselective |
Medium-potency, unselective PDE4 inhibitor |
| Nerandomilast (oral) | Idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases | 3 |
PDE4A: 248 nM PDE4B2: 10 nM cPDE4C2: 8700 nM PDE4D2: 91 nM |
PDE4 A/B = 25 PDE4 A/D = 2.7 PDE4 D/B = 9.1 Selective for B |
Potent, selective PDE4B inhibitor |
| Zatolmilast (oral) | Fragile X syndrome | 2b/3 |
PDE4D2: 127 nM dPDE4D7: 1018 nM ePDE4D7: 8 nM PDE4D3: 7 nM |
ND | Potent allosteric, PDE4D modulator |
| Orismilast (oral) | Psoriasis and atopic dermatitis | 2b |
PDE4A1: 16 nM PDE4A4: 11 nM PDE4A10: 52 nM PDE4B1: 16 nM PDE4B2: 6 nM PDE4B3: 3 nM cPDE4C2: 104 nM PDE4D1: 9 nM PDE4D2: 2 nM PDE4D3: 2 nM PDE4D4: 3 nM PDE4D5: 2 nM PDE4D7: 3 nM |
PDE4 A/B = 3.2 PDE4 A/D = 7.5 PDE4 B/D = 2.5 Selective for B/D |
Potent, selective PDE4B/D inhibitor |
| Crisaborole [30] (topical) | Atopic dermatitis | Approved |
PDE4A1: 52 nM PDE4B1: 61 nM PDE4B2: 75 nM cPDE4C1: 340 nM PDE4D7: 170 nM |
PDE4 B/D = 1.3 PDE4 D/A = 3.3 PDE4 B/D = 1.4 Selective for A |
Medium-potency, selective PDE4A inhibitor |
| PF-07038124 (topical) | Psoriasis and atopic dermatitis | 2b | PDE4B2: 0.5 nM | ND | High-potency PDE4B2 inhibitor |
ND not determined
aUnselective was defined as a potency ratio < three-fold when comparing the isoform with highest potency to the isoform with lowest potency. Selective was defined as a potency ratio ≥ three-fold when comparing the isoform with highest potency to the isoform with lowest potency. When more isoforms were reported within a PDE4 subtype, the average of the isoform data of a given subtype was used
bHigh potency was defined as a potency range of 0.1–0.9 nM. Potent was defined as a potency range of 1–10 nM. Medium potency was defined as a potency range of 11–1000 nM
cPDE4C isoform data are listed in italics and not considered when describing the PDE4 profile, since PDE4C isoforms were reported to be absent in immune and blood cells (see Table 1)
dThis isoform was the basal dimer of PDE4D7
eThis isoform was the activated dimer of PDE4D7
Apremilast data were generated head-to-head with orismilast [26]